The build up of fat-laden deposits on vessel walls as atherosclerotic plaque causes progressive narrowing in the vessel, such as in a carotid or coronary artery. Eventually, lumen or blood flow within the vessel is reduced to such a level that tissue, such as a heart muscle or brain tissue, is starved of oxygen-carrying blood which produces cardiovascular disease resulting in a heart attack, stroke or peripheral ischemia (reduced blood flow to feet or legs). In this process, low-density lipoproteins (LDLs) and immune system cells accumulate in the vessel wall and attract immune system cells into the vessel wall as well. Immune system cells ingest the modified LDLs, giving rise to fatty droplets, which constitute a lipid core of the plaque. The immune system cells secrete enzymes that degrade collagen of the fibrous cap of the plaque and prevent the development of new collagen fibers to repair the cap damage. The weakening of the cap may result in plaque rupture during which the blood of the lumen intermingles with the lipid core, rich in proteins that foster blood coagulation. As a result, a clot forms and the vessel may be occluded. This sudden occlusion of the blood vessel reduces or stops blood flow to the tissue, which results in death of heart muscle or brain tissue due to lack of oxygen-carrying blood resulting in heart attack or stroke. These acute events relating to plaque rupture are the major causes of morbidity and mortality in patients suffering from cardiovascular diseases.
Plaque composition in arteries is indicative of the risk of acute coronary syndromes. Soft plaque includes a high lipid concentration, a thin fibrous cap and inflammatory cells. Plaques with these characteristics are at increased risk for rupture and the associated acute events.
In the past, the build-up of atherosclerotic plaque has been treated by the use of anti-hypercholesterolemia and anti-hyperlipidema agents to prevent the build-up of blood cholesterol. While these agents have been successful in reducing the levels of cholesterol and lipids in the blood, they do not directly treat the underlying causes of plaque rupture which lead to a risk of acute events. Therefore patients treated with existing agents may still be prone to plaque rupture and acute events. In some cases atherosclerotic plaque has been believed to have been caused by influenza viruses resulting in the recommendation of anti-viral drugs for treating atherosclerotic plaque. See Thumpey, Bassler, et al Science vol. 310 pg. 77 (Oct. 7, 2005). Additionally, bacterial infection due to Chlamydia pneumonia has previously been implicated in the development of atherosclerosis and coronary artery disease resulting in the recommendation of antibiotics such as gatifloxacin (N Engl J Med. 2005 Apr. 21; 352(16):1646-54) or azithromycin (Circulation 2000 Oct. 10; 102(15):1755-60) for the treatment of atherosclerotic plaque. However, these agents have not proven to be effective in preventing and reversing plaque build-up. Therefore, it is long to be desired to provide an agent which will be effective preventing and treating cardiovascular diseases caused by atherosclerotic plaque through stabilizing the plaque and as well as preventing the formation of atherosclerotic plaque thereby reducing the risk of plaque rupture and acute events.